The present invention relates to a novel leflunomide Form III and to processes for making leflunomide Forms I, II and III.
Leflunomide (5-methylisoxazole-4-carboxylic acid), having the formula 1: 
is an inhibitor of pyrimidine biosynthesis with antiproliferative activity and is approved in the United States for treatment of rheumatoid arthritis.
The present invention relates to polymorphic forms of leflunomide. Polymorphism is the property of some molecules to adopt more than one crystalline form in the solid state. A single molecule may give rise to a variety of solids having distinct physical properties that can be measured in a laboratory like its thermal behaviorxe2x80x94e.g. melting point and differential scanning calorimetry (xe2x80x9cDSCxe2x80x9d) thermogramxe2x80x94dissolution rate, flowability, X-ray diffraction pattern, infrared absorption spectrum and NMR spectrum. The differences in the physical properties of polymorphs result from the orientation and intermolecular interactions of adjacent molecules in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula which may yet have distinct advantageous and/or disadvantageous physical properties compared to other forms in the polymorph family.
One property of a pharmaceutical compound that can vary depending upon its polymorphic form is its rate of dissolution in aqueous solvent. The rate of dissolution can have therapeutic consequences since it can affect the rate that an orally administered pharmaceutical is delivered to the bloodstream of a patient. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. A more rapidly dissolving form facilitates production of these liquid pharmaceuticals.
U.S. Pat. No. 4,284,786 describes the preparation of leflunomide from 5-methylisoxazole-4-carboxylic acid and 4-trifluoromethylaniline. Leflunomide is obtained from the crude product of Examples a.1-a.7 of the ""786 patent by recrystallization from toluene. The recrystallized product is reproducibly identified by its melting point at 166.5xc2x0 C. U.S. Pat. No. 4,284,786 and the commonly-assigned co-pending U.S. Patent Application Publication No. 2002/0022646 are hereby incorporated by reference for their methods of preparing leflunomide.
According to Australian patent No. AU-A-78870/98, practice of the procedure of the ""786 patent yields leflunomide Form I. The AU-A-78870/98 patent characterizes leflunomide Form I by its X-ray diffraction pattern, which is said to have strong peaks at 16.70, 18.90, 23.00, 23.65 and 29.05xc2x0 at 2xcex8 and weaker peaks at 8.25, 12.65, 15.00, 15.30, 18.35, 21.25, 22.15, 24.10, 24.65, 25.45, 26.65, 27.40, 28.00 and 28.30xc2x0 at 2xcex8.
The AU-A-78870/98 patent further describes leflunomide Form II, which is asserted to be a previously unknown form. According to the AU-A-78870/98 patent, Form II is kinetically stable up to 40xc2x0 C. and more readily dissolves in water than does Form I. Form II is characterized by its X-ray diffraction pattern and IR absorption spectrum. Form II is said to exhibit strong peaks in the powder X-ray diffraction pattern at 10.65, 14.20, 14.80, 16.10, 21.70, 23.15, 24.40, 24.85, 25.50, 25.85, 26.90 and 29.85xc2x0 at 2xcex8 and weaker peaks at 7.40, 9.80, 13.10, 15.45, 16.80, 20.70, 21.45, 22.80, 23.85, 27.25 and 28.95xc2x0 at 2xcex8. The infrared absorption spectrum of Form II is said to have bands at 427, 484, 511, 592, 628, 672, 701, 733, 754, 763, 831, 852, 877, 894, 908, 940, 948, 960, 974, 1014, 1065, 1109, 1160, 1188, 1241, 1264, 1321, 1361, 1384, 1410, 1481, 1536, 1607, 1663, 1691, 1779, 1811, 3065, 3111, 3129, 3201, 3221, 3274, 3297, 3355, 3434 and 3442 cmxe2x88x921.
According to AU-A-78870/98, Form II may be obtained by suspending Form I in water or mixtures of water and C1-C4 alcohols, acetone or methyl ethyl ketone. The suspension may be heated to less than 40xc2x0 C. to accelerate the conversion of Form I to Form II, which takes from 36-65 hours if the suspension is not heated. The Form I and II crystals are not completely dissolved during this process, even with heating, since leflunomide is poorly soluble in these solvents. The process must be monitored by analyzing samples to determine when the conversion is complete. This method is time-consuming because of the low transition rate of the polymorphs.
According to AU-A-78870/98, Form II may also be obtained by rapidly cooling a solution of leflunomide in a C1-C4 alcohol, acetone, methyl ethyl ketone, ethyl acetate, toluene or dichloromethane. Rapid cooling may be achieved by slowly introducing the solution into a cold vessel at a rate that does not warm the vessel to more than xe2x88x9210xc2x0 C. or by spraying into a cold or evacuated chamber. Each method traps the molecules in kinetically favored Form II and each method requires special equipment or materials.
Heating or cooling can be an important factor in the cost of industrial production of pharmaceuticals. Shock cooling requires special equipment and an additional reactor, adding to the cost. The temperature of xe2x88x9210xc2x0 C., which can be achieved by dissolving sodium chloride in ice water, is approximately the lower limit of temperatures that are obtainable without costly equipment or materials. It would be highly desirable to be able to crystallize leflunomide Form II at a temperature of xe2x88x9210xc2x0 C. or above.
One objective of the present invention is to provide an economic process for preparing leflunomide Form II for use in pharmaceutical compositions. We have surprisingly found that leflunomide Form II may be obtained by precipitating leflunomide from a solution in selected polar solvents and mixtures of polar solvents and an xe2x80x9canti-solventxe2x80x9d without resorting to rapid cooling. Optional slow cooling to induce and maximize crystallization of leflunomide Form II may be conducted at temperatures generally above xe2x88x9210xc2x0 C. Leflunomide Form II is thus obtained in good yield. Even in solvent systems wherein the yield of Form II is less than 50%, the unprecipitated leflunomide may be easily recovered and recycled.
The present invention also provides new leflunomide Form III. We have unexpectedly found that a novel form of leflunomide designated Form III is obtained by crystallizing leflunomide according to our process for crystallizing Form II from different solvent systems. Form III is obtained when the solvent is 2-pyrrolidone or a mixture of 2-pyrrolidone and water. It was also found that by heating Form III to about 60xc2x0 C. under vacuum for an extended period of time it transformed into Form I.